1. Field of the Invention
The present invention relates to a method and composition for the topical treatment of cataracts and other complications of diabetes in dogs, and to a method for preparing the composition.
2. Description of the Related Art
In the United States, companion pets number over 62 million dogs and 71 million cats. According to the American Veterinary Medical Association (AVMA), these dogs and cats are living longer due to better nutrition and preventive veterinary care. With over 40% of this population being at least seven years old, more pets are being diagnosed with diabetes mellitus (DM). Although DM occurs at any age, it most frequently is diagnosed in dogs and cats between the ages seven and nine. In 1996, the prevalence of DM in dogs and cats was reported to range between 0.2-1%, i.e., approximately 1 in every 200 dogs and cats was diabetic. A number of complications result from diabetes mellitus, including the formation of cataracts; diabetic retinopathy; corneal lesions, erosion, wound healing complications, epithelial barrier changes, and other corneal pathology; changes in the iris (delay in dilation, fibrous tissue formation, altered vessel permeability, etc.); morphological changes in the ciliary bodies; and other diabetic changes.
Investigations have shown that many of the complications of diabetes result, at least in part, from abnormalities in glucose metabolism through the polyol pathway.
Normally the bulk of intracellular glucose is metabolized to provide energy by phosphorylation of glucose, which is catalyzed by hexokinase to form glucose-6-phosphate, which is further metabolized to useful energy by entry into the Krebs cycle. In the diabetic patient, however, insufficient hexokinase is available to metabolize all of the intracellular glucose.
In many tissues of the body, including lens tissue in the eye, an alternative path is available to metabolize glucose. The enzyme aldose reductase (AR) catalyzes the reduction of glucose to sorbitol with hydrogen supplied by NADPH. Sorbitol is then oxidized to fructose by sorbitol dehydrogenase, the hydrogen being accepted by NAD+. However, in the hyperglycemic patient, although sufficient aldose reductase is available to reduce glucose to sorbitol, there is not sufficient sorbitol dehydrogenase to oxidize the sorbitol to fructose.
This leads to an accumulation of sorbitol in the tissues. Sorbitol does not readily diffuse through the tissues and cellular membranes due to its polarity. It is hypothesized that the accumulation of sorbitol produces a hyperosmotic condition, with resulting fluid accumulation in the cells, altering membrane permeability with the development of the pathological conditions noted above. Consequently, considerable attention has focused on the development of aldose reductase inhibitors (ARIs).
In order to investigate the specific role of AR, researchers have taken advantage of the broad substrate specificity of AR through the use of galactose-fed animals. Experimentally, galactose-induced tissue changes occur faster and progress to a more severe state than glucose-induced changes. This is because (1) intracellular galactose is more rapidly reduced to galactitol by AR than glucose is reduced to sorbitol and (2) higher intracellular levels of polyol are achieved with galactitol, since it is not further metabolized by sorbitol dehydrogenase. While not diabetic, the galactose-fed animal has become a specific model for investigating the role of AR in diabetes-like complications. If AR is involved in the mechanism(s) initiating the diabetic lesion, then the biochemical and pharmacological results obtained with ARIs in the galactose-fed animals should be complementary to that in diabetic animals.
According to one path of ARI development, it was found that certain flavonoids (rutin and hesperidin) having a chroman or chromone ring structure, such as that shown in I below, exhibit ARI activity.

It was then found than the chroman ring structure in combination with a hydantoin structure, shown in II below, produces a spirohydantoin having a greater ARI effect.

Thus, in U.S. Pat. No. 4,130,714, Sarges describes the synthesis of d-6-fluoro-spiro[chroman-4,4′-imidazolidine]-2′,5′-dione, commonly known as sorbinil, shown in III below, and its oral or parenteral administration for the treatment of diabetic complications.

In U.S. Pat. No. 4,540,704, issued Sep. 10, 1985, Ueda et al. describe the preparation of various spirohydantoin compounds, including the compound 6-fluoro-2-methyl-spiro-[chroman-4,4′-imidazolidine]-2′,5′-dione, commonly known as methyl sorbinil or 2-methyl sorbinil, shown in IV below.

The '704 patent recites various experiments on galactosemic rats to show that the compounds described therein are effective in the treatment and prevention of diabetic cataracts, diabetic neuropathy, diabetic nephritis, and various arteriosclerotic blood vessel lesions resulting from diabetes mellitus. The '704 patent notes particularly that 2-methyl sorbinil is 2-10 times more effective than sorbinil in preventing the accumulation of sorbitol, and is also more effective in inhibiting aldose reductase. The patent recites that the compounds may be administered orally, parenterally, or topically, but does not list a formulation of eye drops, a cream, or an ophthalmic gel. It will be noted that 2-methyl sorbinil has two chiral centers, at the 2 position and at 4,4′, and that the synthesis described in the '704 patent results in a mixture of stereoisomers.
Various studies have shown that diabetic cats are not prone to develop sugar cataracts, since the levels of AR in the cat lens is not as high as in dogs of the same age. Diabetic dogs, however, are prone to develop bilateral cataracts, and research as shown that this is related to AR levels in the lens. Research studies have also shown that the oral administration of aldose reductase inhibitors to dogs have been effective in the prevention of cataracts resulting from diabetes, as well as in the treatment of diabetic retinopathy, corneal lesions, and other complications of diabetes mellitus.
Nevertheless, the oral administration of aldose reductase inhibitors has several shortcomings. The dosage of ARIs administered orally is rather high (about four times per day), and must be maintained over a long period of time. Oral administration requires processing by the liver, and may compromise the dog's liver function. Moreover, no studies have yet shown reversal of the formation of cataracts in dogs from the oral administration of aldose reductase inhibitors.
No topical formulation for administering an ARI directly into the dog's eyes is currently known. Conventional topical formulations for ARIs are not effective for use on dogs, since such formulations are generally aqueous solutions, and tear flow in dogs is generally greater than in humans, so that it is not possible to maintain therapeutic levels of an ARI, since such formulations are washed out by tear formation.
A topical formulation for the administration of an ARI directly into a dog's eyes would be desirable for reduction of dosage and frequency of administration, quicker absorption into the system, and avoiding liver metabolism of the ARI. Moreover, a method of preparing such a topical formulation that includes an improved synthesis of 2R-methyl sorbinil having fewer steps and producing greater yield than conventional methods is desired. Thus, a topical treatment of cataracts in dogs solving the aforementioned problems is desired.